This invention relates to a crosslinked hyaluronic acid. More particularly, it is concerned with a crosslinked hyaluronic acid or a salt thereof, which is prepared by crosslinking hyaluronic acid (hereinafter referred to as "HA") or a salt thereof with a polyfunctional epoxy compound.
HA is widely distributed in connective tissues such as skin, vitreous body or hyaloid, umbilical cord, synovial fluid, rooster comb and so on, like acidic mucopolysaccharides such as chondroitin sulfuric acid, heparan sulfuric acid, keratosulfuric acid. Also, HA is present between cells as a complex with protein in tissue, forms a jelly matrix owing to it high water retention and can play an important role in a living body such as maintenance of cell morphology, or protection against attack by bacteria or external power, control of cellular metabolism, lubricating action in joints (K. Meyer, Physiol. Rev., 27, 335, 1947).
As explained above, HA may exert a different action from mucopolysaccharides having a high charging property, which is believed to be derived from a different factor from a simple highly negative charging property, i.e., a high viscoelasticity of HA molecule.
Hitherto, there has been attempted to develop the above-mentioned actions of HA itself, typically, to treat arthritides, to prevent tissue surface from damage by anterior segment surgery in ophthamological field and so on by administering an isolated, purified HA into a living body or a cell system. However, the HA as in a living body may form a complex with certain, special proteins, show a stable and strong stringiness and a high viscoelasticity and play a specific role, whereas the HA as isolated and purified does hardly exert stringiness and it was very difficult in the prior art to extract and purify a highly viscous HA. Moreover, HA is known to undergo enzymatic decomposition or non-enzymatic oxidation-reduction decomposition after being administered to a living body, especially diseased sites (W. Pigman, S. Pizvi and H. L. Holley, Arthritis Rheumatism, 4, 240, 1961) so that it would be difficult to maintain its original viscosity. Satisfactory results have not yet been obtained.
On the other hand, it has been suggested to crosslink dextran or agarose with a crosslinking agent as disclosed in Japanese Patent Published Application No. 1321/1972.
Under these circumstances, we have made earnest studies to obtain a crosslinked HA which shows resistance to enzymatic decomposition or non-enzymatic oxidation-reduction decomposition and, as a result, it has been found that the intended objects can be achieved by crosslinking HA or a salt thereof with a polyfunctional epoxy compound. Further, it has been found that the present crosslinked HA or salts thereof can also show resistance to hyaluronidase and keep various properties of HA itself and thus can have a wide variety of medical and cosmetic uses.